Process for synthesizing carbapenem side chain intermediates

ABSTRACT

A process of synthesizing a compound of the formula I: ##STR1## is described. A compound of the formula II: ##STR2## is reacted with diphenylphosphinic chloride to activate the carboxylic acid group, and then reacted with methanesulfonyl chloride to produce a compound of formula IV: ##STR3## Compound IV is then reacted with Na 2  S in water to produce a compound of formula I.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 08/681,025 filed Jul. 22,1996, now allowed, which is a non-provisional application based uponU.S. application Ser. No. 60/001,891, filed provisionally in the U.S. onAug. 4, 1995, priority of which is claimed hereunder.

BACKGROUND OF THE INVENTION

The present invention relates to the synthesis of carbapenem sidechains, and in particular, to side chains or portions thereof containinga pyrrolidine group, which is bonded to the carbapenem nucleus through athioether linkage. Typically, the pyrrolidine is a portion of the sidechain, and is substituted at the two position with any of a variety ofsubstituents.

Conventionally, these intermediate compounds are prepared from a4-hydroxyproline derivative of the formula: ##STR4## Such syntheticschemes typically require the extensive use of protecting groups.

Similarly, a method of converting trans-4-hydroxy-L-proline to athiolactone of the formula: ##STR5## has been described. However, thisthiolactone is unsuitably protected for large scale synthesis ofcarbapenem antibiotics.

EP 551 993 A1 published on Jul. 21, 1993 relates to a synthesis whichutilizes active esterifying agents and base, followed by treatment withhydrogen sulfide and base.

The present invention is an improvement over these other processes,utilizing an activating agent, namely, diphenylphosphinic chloride,which surprisingly improves the results which are achieved whencommercial quantities are synthesized.

SUMMARY OF THE INVENTION

A process for synthesizing a compound of the formula I: ##STR6## isdescribed wherein P is a protecting group selected fromt-butoxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl andallyloxycarbonyl,

comprising

(a) reacting a compound of formula II: ##STR7## wherein P is aspreviously defined with diphenylphosphinic chloride to produce acompound of formula III: ##STR8##

(b) reacting compound III with methanesulfonyl chloride to produce acompound of formula IV: ##STR9## and

(c) combining compound IV with Na₂ S in water to produce a compound offormula I.

Another aspect of the process described herein relates to a process forproducing a compound of the formula V: ##STR10## wherein P is aprotecting group selected from t-butoxycarbonyl,p-nitrobenzyloxycarbonyl, benzyloxycarbonyl and allyloxycarbonyl;

R¹ and R² are independently selected from hydrogen, aryl and heteroaryl,said aryl and heteroaryl groups being unsubstituted or substituted withfrom 1-3 groups selected from the group consisting of: C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ alkylthio, halo, hydroxy, CO₂ H, CO₂ C₁₋₄ alkyl, NH₂,NHC₁₋₄ alkyl, N(C₁₋₄ alkyl)₂, SO₃ H, CN, SO₂ NH₂, SO₂ C₁₋₄ alkyl, aryland heteroaryl;

comprising: (a) reacting a compound of the formula II: ##STR11## whereinP is as previously defined with diphenylphosphinic chloride to produce acompound of the formula III: ##STR12##

(b) reacting compound III with methanesulfonyl chloride to produce acompound of formula IV: ##STR13##

(c) combining compound IV with Na₂ S in water to produce a compound offormula I: ##STR14##

and (d) reacting compound I with NHR¹ R² wherein R¹ and R² are aspreviously defined to produce a compound of formula V.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions apply to the terms used herein unlessotherwise defined.

Alkyl and the alkyl portions of substituent groups include monovalenthydrocarbon chains containing from 1-4 carbon atoms which are straightor branched as appropriate.

Aryl refers to 6-10 membered mono- and bicyclic ring systems, containingcarbon atoms with alternating (resonating) double bonds. Preferred arylgroups are phenyl and naphthyl.

Heteroaryl refers to aromatic 5-10 membered mono- and bicyclic tingsystems, containing from 1-4 heteroatoms, O, S or N. Preferred nitrogencontaining monocyclic heteroaryl groups include pyridyl, pyrimidinyl,pyrazinyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl and 1, 2,4-triazolyl. Preferred heteroaryl groups containing oxygen as the onlyheterotom include furanyl. Preferred heteroaryl groups containing sulfuras the only heterotom include thienyl.

Preferred bicyclic heteroaryl groups include benzthiazolyl,benzimidazolyl, quinolinyl and isoquinolinyl, indolyl and isoindolyl.

When substituted, the aryl and heteroaryl groups may be substituted with1-3 groups selected from the group consisting of: C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ alkylthio, halo, hydroxy, CO₂ H, CO₂ C₁₋₄ alkyl, NH₂,NHC₁₋₄ alkyl, N(C₁₋₄ alkyl)₂, NHC(O)C₁₋₄ alkyl, SO₃ H, CN, SO₂ NH₂, SO₂C₁₋₄ alkyl, aryl and heteroaryl.

When necessary, the substituents which are optionally present on aryland heteroaryl can be in protected form. Examples of suitable protectinggroups are: t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl,trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl,2,2,2-trichloroethyloxycarbonyl benzhydryl, o-nitrobenzyl,p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl,2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, 2-(trimethylsilyl) ethyl, phenacyl,p-methoxybenzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl, t-butyl andallyloxycarbonyl. Preferred hydroxyl protecting groups aretrimethylsilyl and triethylsilyl. Preferred carboxyl protecting groupsare p-nitrobenzyl and allyl.

Many other suitable hydroxyl and carboxyl protecting groups are known inthe art. See, e.g., Greene, T. W., et al. Protective Groups in OrganicSynthesis, John Wiley & Sons, Inc., 1991.

P represents a protecting group on the proline nitrogen atom. Values ofP are selected from t-butoxycarbonyl (t-BOC), p-nitrobenzyloxycarbonyl,benzyloxycarbonyl and allyloxycarbonyl. The most preferred P groups aret-butoxycarbonyl and p-nitrobenzyloxycarbonyl (PNZ).

Compound II used herein as a starting material is N protectedtrans-4-hydroxy-L-proline. The 2-carboxyl group is activated using thecompound diphenylphosphinic chloride, which is reacted with compound IIin a solvent in the presence of excess base. Solvents which are usefulherein include dichloromethane, acetonitrile, toluene andtetrahydrofuran, or mixtures thereof. Bases which are useful for thisreaction include trialkylamines. Preferred trialkylamines includediisopropylethylamine (DIPEA) and triethylamine.

Typically an amount of diphenylphosphinic chloride which is aboutequimolar to the starting compound can be used. The reaction betweencompound II and diphenylphosphinic chloride is typically run at reducedtemperature, below about 0° C. to as low as about -40° C. Preferably,the reaction temperature is maintained at, about -10° C.

Compound III, with the diphenylphosphinyloxycarbonyl group at positiontwo, is reacted with methanesulfonyl chloride (MsCl) in the same pot toproduce compound IV. This reaction is conducted in a solvent, in thepresence of a slight molar excess of pyridine, collidine, lutidine andthe like, using a slight molar excess of MsCl. This mesylation reactionmay be conducted over about 1-4 hours, at a reduced temperature, e.g.,about 0° C. to as low as about -40° C. Preferably, the reactiontemperature is maintained at about -10° C.

Compound IV is thereafter combined with sodium sulfide and water to formthe thiolactone I. Essentially the reaction can be conducted at about-10° C. to about room temperature. Preferably the sodium sulfide andwater are added quickly, and the reaction is aged for several hours atambient temperature.

After conversion of compound IV to compound I is complete, the latter iscombined in the same pot with ammonia or a primary or secondary amine toform compounds of formula V. At this point, other solvents, such asisopropanol, ethanol, n-propanol, toluene, acetonitrile, ethyl acetateand others are added to improve crystallization of compound V, and thusfacilitate its isolation. Also, addition of a trialkyl or triarylphosphine, e.g., tri-n-butylphosphine, at this stage may be useful inreducing the formation of disulfides corresponding to compound V.

Most primary and secondary amines HNR¹ R² wherein R¹ and/or R² representH, aryl or heteroaryl react with compound I upon slight heating.Generally, the reaction proceeds from about RT to about 100° C. over afew minutes to several hours.

The invention described herein can be conducted in essentially a singlereaction vessel, thus allowing for economical production of compounds Vfrom compound II.

The invention is further illustrated with the following non-limitingexamples.

EXAMPLE ONE ##STR15## A. Synthesis oftrans-N-t-butoxycarbonyl-2-diphenylphosphinyloxycarbonyl-4-hydroxy-L-proline##STR16##

A solution of compound II-a (35.0 g, 151 mmol.) and DIPEA (60 mL, 344mmol) in dry THF (1.0L) was combined over 20 min with a solution ofdiphenylphosphinic chloride (37.5 g, 155 mmol) in THF (50 mL) at -20° C.The reaction mixture was stirred at -20° C. for 90 minutes to producecompound III-a, which can be isolated and characterized or used in thenext part without isolation.

B. Synthesis oftrans-N-t-butoxycarbonyl-2-diphenylphosphinyloxycarbonyl-4-methanesulfonyloxy-L-proline##STR17##

Without isolation and characterization, after stirring the reactionmixture from part A for 90 minutes at -20° C., pyridine (13.0 mL, 161mmol) was added followed by a solution of methanesulfonyl chloride (19.8g, 171 mmol) in THF (50 mL) over 15 minutes. The reaction mixture wasstirred at -20° C. for 2 hours and allowed to warm to -5° C. over anadditional 30 minutes producing compound IV-a. The methanesulfonylsubstituted compound can be isolated and characterized, or used in thenext reaction without isolation and characterization.

C. Synthesis of N-t-butoxycarbonyl-2-thia-5-azabicyclo2.2.1!heptan-3-one ##STR18##

After allowing the reaction from part B to warm to -5° C., a solution ofNa₂ S.H₂ O (45.0 g, 187 mmol) in H₂ O (60 mL) was added in one portionproducing a biphasic reaction mixture. The biphasic mixture was allowedto warm to room temperature and was stirred for 6 hrs. The resultingsuspension was then partitioned between toluene and water.

The organic layer was washed with HCl (2.0M), NaHCO₃ (1.0M) and brine,dried over MgSO₄ and concentrated in vacuo to produce an oily residue.Crystallization of the oily residue from ether/ethyl acetate providedthe title compound (29.4 g, 88 mmol).

mp 91° C.; α!_(D) =-88.0° (C=1.01; CHCl₃). ¹ H-NMR (CD₂ Cl₂, -20° C.;400 MHz) δ1.42 (s,³ H), 2.07 (dt, J 2.5, J 11.3, 1H),2.13 (m, J 11.3,1H),3.48 and3.53 (m, J 1.1,J 10.2, 1H), 3.74, (m, J 2.8, J 10.1, 1H),4.11 (m, 1H), 4.42 and 4.53 (m, J 0.9, 1H); ¹³ C-NMR (CD₂ Cl₂, -20° C.;100 MHz) δ29.9/30.0 (q), 43.3/43.9 (l), 49.9/50.6 (d), 54.3/54.7 (t),65.3/66.1 (d), 82.5/82.6 (s), 155.5/155.7 (s), 201.1/201.6 (s).

EXAMPLE TWO ##STR19##

Thiolactone I-a from Example One without isolation, can be combined withthe amine shown below in column one to produce the cis N-protected4-thiol substituted proline derivative shown below in column two.

                                      TABLE ONE                                   __________________________________________________________________________    Amine         Product V-a                                                     __________________________________________________________________________    (1) NH.sub.4 Cl                                                                              ##STR20##                                                       ##STR21##                                                                                   ##STR22##                                                       ##STR23##                                                                                   ##STR24##                                                       ##STR25##                                                                                   ##STR26##                                                      __________________________________________________________________________     (1) 4.0 eq. of NH.sub.4 Cl in Et.sub.3 N; solvent CH.sub.3 OH; reaction       time: 30 min at RT;                                                           (2) 1.25 eq. of aniline; solvent toluene; reaction time: 2 hrs at             100° C.;                                                               (3) 1.25 eq. of 3aminobenzoic acid; solvent toluene; reaction time: 2 hrs     at 100° C.;                                                            (4) 1.25 eq. of 5amino-2-carboxythiophene; solvent toluene; 2 hrs at          100° C.;                                                          

EXAMPLE THREE

Using the procedures set forth in Example One, Part A, the compounds ofcolumn one are reacted with diphenylphosphinic chloride to produce thecompounds in column two.

                                      TABLE TWO                                   __________________________________________________________________________     ##STR27##                                                                                        ##STR28##                                                  ##STR29##                                                                                        ##STR30##                                                  ##STR31##                                                                                        ##STR32##                                                 __________________________________________________________________________

EXAMPLE FOUR

Using the procedures set forth in Example One, Part B, the compounds ofcolumn one are reacted with methanesulfonyl chloride to produce thecompounds in column two.

                  TABLE THREE                                                     ______________________________________                                        (III-b)                                                                                   ##STR33##                                                         (III-c)                                                                                   ##STR34##                                                         (III-d)                                                                                   ##STR35##                                                         ______________________________________                                    

EXAMPLE FIVE

Using the procedures set forth in Example One, Part C, the compounds ofcolumn one are reacted with Na₂ S in water to produce the compounds incolumn two.

                  TABLE FOUR                                                      ______________________________________                                        (IV-b)                                                                                     ##STR36##                                                        (IV-c)                                                                                     ##STR37##                                                        (IV-d)                                                                                     ##STR38##                                                        ______________________________________                                    

EXAMPLE SIX

Using the procedures set forth in Example Two, the compounds of columnone are reacted with the amine in column two to produce the compounds incolumn three.

                                      TABLE FIVE                                  __________________________________________________________________________    Amine NHR.sup.1 R.sup.2                                                                       Pyrrolidine                                                   __________________________________________________________________________    (I-b)                                                                            (1) NH.sub.4 Cl                                                                             ##STR39##                                                    (I-b)                                                                             ##STR40##                                                                                  ##STR41##                                                    (I-b)                                                                             ##STR42##                                                                                  ##STR43##                                                    (I-b)                                                                             ##STR44##                                                                                  ##STR45##                                                    (I-c)                                                                            (1) NH.sub.4 Cl                                                                             ##STR46##                                                    (I-c)                                                                             ##STR47##                                                                                  ##STR48##                                                    (I-c)                                                                             ##STR49##                                                                                  ##STR50##                                                    (I-c)                                                                             ##STR51##                                                                                  ##STR52##                                                    (I-d)                                                                            (1) NH.sub.4 Cl                                                                             ##STR53##                                                    (I-d)                                                                             ##STR54##                                                                                  ##STR55##                                                    (I-d)                                                                             ##STR56##                                                                                  ##STR57##                                                    (I-d)                                                                             ##STR58##                                                                                  ##STR59##                                                    __________________________________________________________________________     1: Trin-butylphosphine may be added.                                     

While certain preferred embodiments have been described herein indetail, numerous alternative embodiments are contemplated as fallingwithin the scope of the invention.

What is claimed is:
 1. A process of producing a compound of the formulaV: ##STR60## wherein P is a protecting group selected fromt-butoxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl andallyloxycarbonyl;R¹ and R² are independently selected from hydrogen,aryl and heteroaryl, said aryl and heteroaryl groups being unsubstitutedor substituted with from 1-3 groups selected from the group consistingof: C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, halo, hydroxy, CO₂ H, CO₂C₁₋₄ alkyl, NH₂, NHC₁₋₄ alkyl, N(C₁₋₄ alkyl)₂, SO₃ H, CN, SO₂ NH₂, SO₂C₁₋₄ alkyl, aryl and heteroaryl; comprising: (a) reacting a compound ofthe formula II: ##STR61## wherein P is as previously defined withdiphenylphosphinic chloride to produce a compound of the formula III:##STR62## (b) reacting compound III with methanesulfonyl chloride toproduce a compound of formula IV: ##STR63## (c) combining compound IVwith Na₂ S in water to produce a compound of formula I: ##STR64## and(d) reacting compound I with NHR¹ R² wherein R¹ and R² are as previouslydefined to produce a compound of formula V.
 2. A process in accordancewith claim 1 wherein compound II is reacted with diphenylphosphinicchloride in the presence of a base.
 3. A process in accordance withclaim 2 wherein the base is a trialkylamine.
 4. A process in accordancewith claim 3 wherein the trialkylamine is selected from the groupconsisting of diisopropylethylamine and triethylamine.
 5. A process inaccordance with claim 1 wherein compound III is reacted withmethanesulfonyl chloride to produce a compound of formula IV in thepresence of a base.
 6. A process in accordance with claim 5 wherein thebase is selected from the group consisting of pyridine, collidine andlutidine.
 7. A process in accordance with claim 1 wherein P representst-butoxycarbonyl or p-nitrobenzyloxycarbonyl.
 8. A process in accordancewith claim 1 wherein NHR¹ R² is selected from the group consisting of:##STR65##